title: Involvement of the TGF-beta and beta-catenin pathways in pelvic lymph node metastasis in early-stage cervical cancer.
abstract: OBJECTIVE
  Presence of pelvic lymph node metastases is the main prognostic factor in early-stage cervical cancer patients, primarily treated with surgery. Aim of this study was to identify cellular tumor pathways associated with pelvic lymph node metastasis in early-stage cervical cancer.
  
  
  METHODS
  Gene expression profiles (Affymetrix U133 plus 2.0) of 20 patients with negative (N(0)) and 19 with positive lymph nodes (N(+)), were compared with gene sets that represent all 285 presently available pathway signatures. Validation immunostaining of tumors of 274 consecutive early-stage cervical cancer patients was performed for representatives of the identified pathways.
  
  
  RESULTS
  Analysis of 285 pathways resulted in identification of five pathways (TGF-β, NFAT, ALK, BAD, and PAR1) that were dysregulated in the N(0), and two pathways (β-catenin and Glycosphingolipid Biosynthesis Neo Lactoseries) in the N(+) group. Class comparison analysis revealed that five of 149 genes that were most significantly differentially expressed between N(0) and N(+) tumors (P < 0.001) were involved in β-catenin signaling (TCF4, CTNNAL1, CTNND1/p120, DKK3, and WNT5a). Immunohistochemical validation of two well-known cellular tumor pathways (TGF-β and β-catenin) confirmed that the TGF-β pathway (positivity of Smad4) was related to N(0) (OR: 0.20, 95% CI: 0.06-0.66) and the β-catenin pathway (p120 positivity) to N(+) (OR: 1.79, 95%CI: 1.05-3.05).
  
  
  CONCLUSIONS
  Our study provides new, validated insights in the molecular mechanism of lymph node metastasis in cervical cancer. Pathway analysis of the microarray expression profile suggested that the TGF-β and p120-associated noncanonical β-catenin pathways are important in pelvic lymph node metastasis in early-stage cervical cancer.
authors.affiliation: Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Maartje G
authors.initials: MG
authors.lastname: Noordhuis
authors.forename: Rudolf S N
authors.initials: RS
authors.lastname: Fehrmann
authors.forename: G Bea A
authors.initials: GB
authors.lastname: Wisman
authors.forename: Esther R
authors.initials: ER
authors.lastname: Nijhuis
authors.forename: Jelmer J
authors.initials: JJ
authors.lastname: van Zanden
authors.forename: Perry D
authors.initials: PD
authors.lastname: Moerland
authors.forename: Emiel
authors.initials: E
authors.lastname: Ver Loren van Themaat
authors.forename: Haukeline H
authors.initials: HH
authors.lastname: Volders
authors.forename: Mirjam
authors.initials: M
authors.lastname: Kok
authors.forename: Klaske A
authors.initials: KA
authors.lastname: ten Hoor
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: Geertruida H
authors.initials: GH
authors.lastname: de Bock
authors.forename: Ate G J
authors.initials: AG
authors.lastname: van der Zee
authors.forename: Ed
authors.initials: E
authors.lastname: Schuuring
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051177:Catenins / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D000095002:Delta Catenin
chemical_list: D051177:Catenins; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D000095002:Delta Catenin